title: Diabetes mellitus without metformin intake is associated with worse oncologic outcomes after radical nephroureterectomy for upper tract urothelial carcinoma.
abstract: OBJECTIVE
  Evidence suggests a detrimental effect of diabetes mellitus (DM) on cancer incidence and outcomes. To date, the effect of DM and its treatment on prognosis in upper tract urothelial carcinoma (UTUC) remains uninvestigated. We tested the hypothesis that DM and metformin use impact oncologic outcomes of patients treated with radical nephroureterectomy (RNU) for UTUC.
  
  
  METHODS
  Retrospective analysis of 2492 patients with UTUC treated at 23 institutions with RNU without neoadjuvant therapy. Cox regression models addressed the association of DM and metformin use with disease recurrence, cancer-specific mortality and any-cause mortality.
  
  
  RESULTS
  A total of 365 (14.3%) patients had DM and 194 (7.8%) patients used metformin. Within a median follow-up of 36 months, 663 (26.6%) patients experienced disease recurrence, 545 patients (21.9%) died of UTUC and 884 (35.5%) patients died from any cause. Diabetic patients who did not use metformin were at significantly higher risk of disease recurrence and cancer-specific death compared to non-diabetic patients and diabetic patients who used metformin. In multivariable Cox regression analyses, DM treated without metformin was associated with worse recurrence-free survival (HR: 1.44, 95% CI 1.10-1.90, p = 0.009) and cancer-specific mortality (HR: 1.49, 95% CI 1.11-2.00, p = 0.008).
  
  
  CONCLUSIONS
  Diabetic UTUC patients without metformin use have significantly worse oncologic outcomes than diabetics who used metformin and non-diabetics. The possible mechanism behind the impact of DM on UTUC biology and the potentially protective effect of metformin need further elucidation.
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA; Department of Urology, University Hospital Basel, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Rieken
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA; Department of Urology, Cochin Hospital, APHP, Paris Descartes University, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Xylinas
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA; Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Kluth
authors.affiliation: Division of Urologic Surgery and Center for Surgery and Public Health, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Q-D
authors.initials: QD
authors.lastname: Trinh
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Lee
authors.affiliation: Department of Urology, Medical University of Vienna, Vienna, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Fajkovic
authors.affiliation: Department of Surgical, Oncological and Gastroenterologic Sciences, Urology Clinic, University of Padua, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Novara
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: V
authors.initials: V
authors.lastname: Margulis
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Lotan
authors.affiliation: Department of Urology, Hospital Universitario Puerta de Hierro-Majadahonda, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: J I
authors.initials: JI
authors.lastname: Martinez-Salamanca
authors.affiliation: Department of Urology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Urology, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Seitz
authors.affiliation: Department of Urology, Landesklinikum Korneuburg, Korneuburg, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Remzi
authors.affiliation: Department of Urology, University of Montreal, Montreal, QC, Canada.
authors.forename: P I
authors.initials: PI
authors.lastname: Karakiewicz
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Scherr
authors.affiliation: Department of Urology, Vita-Salute University, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Briganti
authors.affiliation: Unit of Gender Medicine, Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Kautzky-Willer
authors.affiliation: Department of Urology, University Hospital Basel, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Bachmann
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA; Department of Urology, Medical University of Vienna, Vienna, Austria. Electronic address: sfshariat@gmail.com.
authors.forename: S F
authors.initials: SF
authors.lastname: Shariat
mesh_terms: D000368:Aged; D002295:Carcinoma, Transitional Cell / Q000150:complications / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D003920:Diabetes Mellitus / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000150:complications / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D008207:Lymphatic Metastasis; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009392:Nephrectomy; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016896:Treatment Outcome; D014516:Ureteral Neoplasms / Q000150:complications / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D018666:Ureteroscopy; D013520:Urologic Surgical Procedures
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin
keywords: Diabetes mellitus; Metformin; Surgery; Upper tract urothelial carcinoma